Basal cell carcinoma has low immunogenicity. Tumor cells specific Foxc1 protein (pink), which suppresses HLA class I (inexperienced) within the tumor cells. Credit score: Shawn Demehri, Massachusetts Basic Hospital
Compromised antigen presentation ranks among the many high mechanisms that render cancers non-immunogenic (non-responsive to immune-based therapies). Regardless of harboring the very best tumor mutational burden of all cancers, basal cell carcinomas (BCCs) have low immunogenicity.
Lack of human leukocyte antigens class I (HLA-I) elements is especially prevalent in immune-excluded cancers.
Tumor antigens are captured and displayed by antigen processing and presentation equipment (APM) on the cell floor by HLA-I, making it doable for CD8+ T cells to get rid of most cancers cells. Nevertheless, most cancers cells have developed numerous means to restrict APM and evade immune recognition.
Shawn Demehri, MD, Ph.D., a physician-investigator within the Cutaneous Biology Analysis Middle and Krantz Household Middle for Most cancers Analysis at Massachusetts Basic Hospital and an Affiliate Professor of Dermatology at Harvard Medical Faculty, is the senior creator of a research in Cell Reviews, titled “Epigenomic Regulation of Stemness Contributes to the Low Immunogenicity of the Most Mutated Human Cancer.”
To find out BCC’s immune state, Demehri’s analysis group studied a big assortment of main human BCCs in comparison with squamous cell carcinomas (SCCs), which have confirmed extra conscious of immune-based therapies. They found that main BCCs had an immune-excluded phenotype related to minimal HLA-I expression by most cancers cells, even throughout their early growth.
The researchers additionally decided {that a} stem-like quiescent program that persevered from the tumor’s cell of origin suppressed APM genes in BCC cells, and that epigenomic reversal of APM gene suppression enabled BCC immunotherapy.
These findings reveal the cell of origin because the dominant determinant of most cancers immunogenicity in BCCs and level to a brand new method that might enhance therapy.
Keratinocyte carcinoma, together with BCCs and cutaneous SCCs, is the most typical most cancers with a steady rise in incidence.
SCCs present a 49.3% goal response fee to PD-1 remedy, whereas metastatic BCC has solely a 21% ORR to anti-PD-1 remedy.
Organ transplant recipients on systemic immunosuppressants have over 100 occasions larger threat of SCCs in comparison with the final inhabitants however solely a six to 16 occasions larger threat of BCC, suggesting that BCC could lack immunogenicity.
Demehri explains, “To find out BCC’s immune state, we studied a big assortment of main human BCCs in contrast with SCCs. Though T cells have been detectable within the stroma surrounding the BCC, considerably fewer CD4+ and CD8+ T cells infiltrated into BCC tumor foci in contrast with SCCs. A survey of different immune cells discovered that they have been additionally considerably decreased in BCC in comparison with SCC.
“Single-cell RNA sequencing on BCC and SCC samples collected with related cell preparation strategies confirmed a lot smaller immune cell populations in BCC in comparison with SCC. These findings point out that main BCC has an immune-excluded phenotype, which results in low immunogenicity of BCC in contrast with ‘immune infiltrated’ SCC.
“Importantly, early BCC with uncommon T cells within the stroma confirmed low HLA-I expression, indicating that low APM ranges in BCC originate from an intrinsic mechanism integral to its developmental biology.
“We also found Foxc1 is a critical suppressor of IRF1 and HLA-I in BCC cells, reminiscent of its function in quiescent hair follicle stem cells. Foxc1 downregulates IRF1 and HLA-I expression by epigenomic mechanisms, which can be reversed to enable BCC immunotherapy.”
Medical implications
“We demonstrate that topical entinostat treatment upregulates antigen presentation in BCC in vivo,” Demehri continues. “As such, combining entinostat with topical and systemic immunotherapy is essential to enabling BCC immunotherapy.
“To perform this, we mixed topical entinostat with an FDA-approved topical immunotherapy, imiquimod. The excessive efficacy of entinostat plus imiquimod in suppressing BCC growth signifies that entinostat-induced APM expression in BCC most cancers cells synergizes with immune cell activation by imiquimod to get rid of BCC in vivo.
“Based on our findings, a first-in-human clinical trial is warranted to investigate the efficacy of this combination therapy for BCC treatment in humans.”
Extra data:
Tomonori Oka et al, Epigenomic regulation of stemness contributes to the low immunogenicity of essentially the most mutated human most cancers, Cell Reviews (2025). DOI: 10.1016/j.celrep.2025.115561
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Basal cell carcinoma’s low immunogenicity linked to suppression of antigen presentation from its cell of origin (2025, April 22)
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